This invention relates to certain 1,2-benzothiazines which demonstrate selective 5-lipoxygenase (5-LO) pathway inhibitory activity. More particularly it relates to certain substituted-4-hydroxy- and 4-acyloxy-2H-1,2-benzothiazine 1,1-dioxides having at the 3-position a 2-substituted-1,3,4-oxadiazol-5-yl, a 2-substituted-tetrazol-5-yl or a 1-substituted-tetrazol-5-yl group.
Arachidonic acid is the biological precursor of a group of endogenous metabolites, the leukotrienes. Said metabolites arise via the action of arachidonate lipoxygenases and give rise to allergic reactions. 5-Lipoxygenase, for example, catalyzes the oxygenation of arachidonic acid at C.5. This is the first step in the biosynthesis of slow reacting substance of anaphylaxis (SRS-A), a bronchoconstrictive agent believed to cause allergic asthma in man.
Although discovery of the antiinflammatory activity of 1,2-benzothiazines has given rise to intensive investigation of said compounds, especially of the 1,1-dioxide derivatives thereof wherein the substituent at the 3-position is a substituted carboxamide, no one appears to have synthesized 1,2-benzothiazines having a heterocyclic moiety at the 3-position, or to have disclosed the use of 1,2-benzothiazines as inhibitors of 5-lipoxygenase.
The 5-LO inhibiting activity of several structural types of compounds is reported in the literature:
2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861), Yoshimoto et al., Biocnim. et Biophys. 713, 470-473 (1982) and analogs thereof; PA0 5,6-methanoleukatriene derivatives including KCN-TEI-6172, and 5,8,11-eicosatriynoic acid (ETYA); PA0 3-amino-1-(m-trifluoromethyl)phenyl-2-pyrazoline (BW 755c), Krishishara et al., FEBS Letters, 143, 13-16 (1982); PA0 1-phenyl-3-pyrazolidone (Phenidone), Carty et al., Prostaglandins, 19, 671-679 (1980); PA0 6,9-pyrroloprostacyclin (U-60,257), Bach et al., Prostaglandins, 23, 759-771 (1982); and PA0 tetrazole, acylhydroxylamine, hydroxymethylketone and amide derivatives of unsaturated fatty acids related to arachidonic acid, EP-104,468, published Apr. 14, 1984. PA0 R.sup.2 is hydrogen, alkanoyl having from 2 to 15 carbon atoms, cycloalkylcarbonyl having from 3 to 8 carbon atoms in the cycloalkyl moiety, benzoyl or benzoyl ring substituted with F, Cl, Br, I, CF.sub.3, CH.sub.3, NO.sub.2 or CH.sub.3 O; and PA0 R.sup.3 is alkyl having from 1 to 15 carbon atoms, thienyl, furyl, cycloalkyl having from 3 to 8 carbon atoms, phenyl or phenyl substituted with F, Cl, Br, I, CF.sub.3, CH.sub.3 or CH.sub.3 O; and wherein in formula II, R.sup.1 is as defined above; PA0 R.sup.4 is hydrogen, alkanoyl having from 2 to 15 carbon atoms, benzoyl or benzoyl ring substituted with F, Cl, Br, I, CF.sub.3, CH.sub.3 or CH.sub.3 O; and PA0 R.sup.5 is hydrogen, alkyl having from 1 to 15 carbon atoms, alkanoyl having from 2 to 15 carbon atoms, alkenyl, aralkenyl, cycloalkyl of from 3 to 8 carbon atoms, phenylethyl, cycloalkylcarbonyl having from 3 to 8 carbon atoms in the cycloalkyl moiety, benzoyl, benzoyl substituted with F, Cl, Br, I, CF.sub.3, CH.sub.3, CH.sub.3 O or NO.sub.2, furylmethyl, thienylmethyl, benzyl or benzyl ring substituted with F, Cl, Br, I, CF.sub.3, CH.sub.3, NO.sub.2 or CH.sub.3 O. PA0 R.sup.1 is alkyl having from 1 to 4 carbon atoms or methoxyethoxymethyl; PA0 R.sup.2 is hydrogen, alkanoyl having from 2 to 15 carbon atoms, benzoyl, cyclohexylcarbonyl or methoxybenzoyl; PA0 and R.sup.3 is alkyl having from 7 to 15 carbon atoms, phenyl, methoxyphenyl, tolyl or cyclohexyl; and of formula II, wherein R.sup.1 is alkyl having from 1 to 3 carbon atoms or methoxyethoxymethyl; PA0 R.sup.4 is hydrogen, acetyl or benzoyl; and PA0 R.sup.5 is hydrogen, alkyl having 7 to 15 carbon atoms, benzyl, methylbenzyl or methoxybenzyl.
The overall medical significance of the problems of bronchoconstriction and pulmonary diseases gives rise to the need for selective and efficient inhibitors of 5-LO in order to prevent, or at least to minimize, the formation of SRS-A in man and, as a consequence, to reduce allergic asthma reactions.